Nitriles are important intermediates that have extremely diverse uses in organic synthesis. Both compound classes exhibit high reactivity of the C,N multiple bond, as a result of which countless heterocarbonyl reactions are made possible. The significance in modern organic synthesis is restricted only by limitations of accessibility of these compound classes. Standard processes for preparing nitrites are dehydrations of carboxamides, where countless reagents, such as, for example, POCl3 can be used.
In modern organic synthesis, the importance of chemoselective, regioselective and stereoselective reagents is increasing explosively. If, for example, it is desired, in a complex molecule with numerous functional groups, some of which only have slight reactivity differences, to convert a certain acid group into an amide without influencing other groups (e.g. epimerization of chiral functionalities), it is no longer possible to use unselective methods such as SOCl2. A highly selective reagent for the extremely selective amide bond linkage, which produces excellent selectivities and yields without epimerization even in oligopeptides, is propanephosphonic anhydride (T3P®). This reagent is commercially available in various solvents and is easy to use. The performance of this reagent is so high that the problem of linking amide and peptide bonds in complex molecules can nowadays be considered solved.
A comparable solution for converting carboxylic acids and N-alkylcarboxamides into the corresponding nitriles has hitherto been lacking. Although the known reagents can bring about the desired transformations, other groups are often likewise influenced in the process. In many cases, even distant stereocenters are epimerized as a result of the drastic conditions required.
It would therefore be very desirable to have a process which can convert carboxylic acids and N-alkyl-carboxamides into the corresponding nitrites by dehydration, but which at the same time has very high chemoselectivities, and can additionally be used in economically feasible processes. The known reagents do not solve this problem as will be demonstrated by a few examples: although POCl3 in combination with bases can bring about the specified reactions, almost every possible functional group likewise reacts with this reagent. Using dicyclohexylcarbodiimide (DCC), it is likewise possible to carry out the desired transformation to nitriles, although partial epimerizations often occur in the process; even worse, however, are often the properties of the dicyclo-hexylurea formed as by-product, which can often only be separated from the product with difficulty, and then only by chromatographic separations. The use of water-soluble DCC derivatives is in most cases not economically feasible due to their very high cost and difficult accessibility.